U.S. patent number 3,969,502 [Application Number 05/486,757] was granted by the patent office on 1976-07-13 for method for contraception by the administration of sequential contraceptive preparations.
This patent grant is currently assigned to Schering Aktiengesellschaft. Invention is credited to Ursula Lachnit-Fixson.
United States Patent |
3,969,502 |
Lachnit-Fixson |
* July 13, 1976 |
Method for contraception by the administration of sequential
contraceptive preparations
Abstract
Method of contraception over a 21-day cycle in which an estrogen
and a progestogen are administered in a low dosage for 10-12 days
and thereafter at a slightly higher dosage for the next 11-9
days.
Inventors: |
Lachnit-Fixson; Ursula (Berlin,
DT) |
Assignee: |
Schering Aktiengesellschaft
(Berin & Bergkamen, DT)
|
[*] Notice: |
The portion of the term of this patent
subsequent to February 17, 1993 has been disclaimed. |
Family
ID: |
27431476 |
Appl.
No.: |
05/486,757 |
Filed: |
July 9, 1974 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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350590 |
Apr 12, 1973 |
3939264 |
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Foreign Application Priority Data
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Apr 14, 1972 [DT] |
|
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2218831 |
Mar 3, 1973 [DT] |
|
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2310963 |
Jul 9, 1973 [DT] |
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2335265 |
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Current U.S.
Class: |
514/170;
514/843 |
Current CPC
Class: |
A61K
31/565 (20130101); A61K 31/57 (20130101); A61K
31/57 (20130101); A61K 31/565 (20130101); A61K
31/57 (20130101); A61K 31/57 (20130101); A61K
31/57 (20130101); A61K 2300/00 (20130101); Y10S
514/843 (20130101) |
Current International
Class: |
A61K
31/57 (20060101); A61K 31/565 (20060101); A61K
031/56 () |
Field of
Search: |
;424/239,241 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Roberts; Elbert L.
Attorney, Agent or Firm: Millen, Raptes & White
Parent Case Text
BACKGROUND OF THE INVENTION
This is a continuation-in-part of application Ser. No. 350,590,
filed Apr. 12, 1973, now U.S. Pat. No. 3,939,264.
Claims
What is claimed is:
1. A method of contraception wherein a combination of an estrogen
and a progestogen is administered orally to a female of
child-bearing age for about 21 days and for the next 5-7 days, for
a total of about 28 days, no estrogens and progestogens are
administered, which comprises administering orally daily for the
first 10-12 days either a combination of:
a. 0.030 mg. of 17.alpha.-ethinylestradiol and
0.050 mg. of d-norgestrel,
or a combination of:
b. 0.030 mg. of 17.alpha.-ethinylestradiol and
1 mg. of 17.alpha.-ethinyl-19-nortestosterone acetate;
and then administering orally daily for the next 11-9 days, when
combination (a) is administered for the first 10-12 days, a
combination of
c. 0.040 mg. of 17.alpha.-ethinylestradiol and
0. 125 mg. of d-norgestrel,
or when combination (b) is administered for the first 10-12 days, a
combination either of:
d. 0.050 mg. of 17.alpha.-ethinylestradiol and
2 mg. of 17-ethinyl-19-nortestosterone acetate; or
e. 0.050 mg. of 17-ethinylestradiol and
2 mg. of cyproterone acetate.
2. A method according to claim 1 wherein for the first 10-12 days
0.030 mg. of 17.alpha.-ethinylestradiol and 0.050 mg. of
d-norgestrel are administered daily and for the next 11-9 days
0.040 days 0.040 mg. of 17-ethinylestradiol and 0.125 mg. of
d-norgestrel are administered daily.
3. A method according to 1 wherein for the first 10-12 days 0.030
mg. of 17.alpha.-ethinylestradiol and 1 mg. of
17.alpha.-ethinyl-19-nortestosterone acetate is administered daily
and for the next 11-9 days 0.050 mg. of 17.alpha.-ethinylestradiol
and 2 mg. of 17.alpha.-ethinyl-19-nortestosterone acetate are
administered daily.
4. A method according to claim 1 wherein for the first 10-12 days
0.030 mg. of 17.alpha.-ethinylestradiol and 1 mg. of
17.alpha.-ethinyl-19-nortestosterone acetate is administered daily
and for the next 11-9 days 0.050 mg. of 17.alpha.-ethinylestradiol
and 2 mg. of cyproterone acetate are administered daily.
5. A two-stage combination oral contraceptive composition
comprising about 21 daily doses of a contraceptively effective
combination of an estrogen a progestogen consisting essentially of,
in a first stage of 10-12 successive units, a combination of:
a. 0.030 mg. of 17.alpha.-ethinylestradiol and
0.050 mg. of d-norgestrel,
or a combination of
b. 0.030 mg. of 17.alpha.-ethinylestradiol and
1 mg. of 17.alpha.-ethinyl-19-nortesterone acetate;
and, in a second stage of 11-9 successive units, a combination,
when the first stage is combination (a), of
c. 0.040 mg. of 17.alpha.-ethinylestradiol and
0.125 mg. of d-norgestrel
or a combination, when the first state is combination (b), either
of:
d. 0.050 mg. of 17.alpha.-ethinylestradiol and
2 mg. of 17-ethinyl-19-nortestosterone acetate; or
e. 0.050 mg. of 17-ethinylestradiol and
2 mg. of cyproterone acetate.
6. A contraceptive composition according to claim 5 wherein the
estrogen and progestogen are in tablet form.
7. A contraceptive composition according to claim 5 wherein in the
first stage, the estrogen is 0.030 mg. of
17.alpha.-ethinylestradiol and the progestogen is 0.050 mg. of
d-norgestrel per unit dosage and, in the second state, 0.040 mg. of
17.alpha.-ethinylestradiol and 0.125 mg. of d-norgestrel per unit
dosage.
8. A contraceptive composition according to claim 5 wherein, in the
first stage, the estrogen is 0.030 mg. of
17.alpha.-ethinylestradiol and the progestogen is 1 mg. of
17.alpha.-ethinyl-19-nortestosterone acetate per unit dosage and,
in the second stage, 0.050 mg. of 17.alpha.-ethinylestradiol and 2
mg. of 17.alpha.-ethinyl-19-nortestosterone acetate per unit
dosage.
9. A contraceptive composition according to claim 5 containing, in
the first stage 0.030 mg. of 17.alpha.-ethinylestradiol and 1 mg.
of 17.alpha.-ethinyl-19-nortestosterone acetate per unit dosage
and, in the second stage, 0.050 mg. of 17.alpha.-ethinylestradiol
and 2 mg. of cyproterone acetate per unit dosage.
Description
Numerous hormonal methods for contraception are known, i.e.., the
oral administration of combination-type preparations, e.g.,
"Ovulen," "Anovlar," "Lyndiol," and similar combinations of
estrogenic and gestagenic active agents. Also conventional is the
administration of purely sequential preparations such as, for
example, "Ovanone," etc., wherein first an estrogen is administered
at a high dosage in the absence of gestagen, over a period of 7
days, and thereafter the estrogen is administered at the same high
dosage in combination with a relatively high amount of gestagen
over a period of 15 days, with the next 6 days being a blank period
without administration of estrogenic or gestagenic agent in order
to mimic the normal 28-day menstrual cycle of the woman.
The administration of modified sequential preparations is likewise
conventional, such as, for example, "Kombiquens," "Tri-Ervonum,"
and "Oraconal," etc., wherein first an estrogen is administered at
a high dosage in combination with a low amount of gestagen over a
period of 16 days, and subsequently the estrogen is administered
over a period of about 7 days at the same high dosage in
combination with an amount of gestagen about 5-10 times the
original amount. See U.S. Pat. No. 3,568,828. To adapt to the
natural 28-day cycle of the female, a 5-day hormone-free period
follows the administration of these preparations wherein placebos
or any desired other non-contraceptive effective agents are taken,
such as, for example, tonics, iron supplements, etc.
The disadvantages of the administration of the above-mentioned
sequential preparations are, in particular, the relatively high
doses of estrogen, resulting, in addition to evoking the customary
symptoms caused by an excess of estrogen, such as, for example,
gastrointestinal disturbances, nausea, weight gain from edema,
etc., along with an increase in the risk of thromboembolism. On the
other hand, however, it was considered essential to ingest high
doses of estrogen for reliable contraceptive effect.
SUMMARY OF THE INVENTION
According to this invention, reliable contraception is achieved by
first administering as a first stage a combination of an estrogen
and a progestogen both at a lower but contraceptively effective
daily dosage over a period of 10-12 days and then for the next 11-9
days, administering as a second stage a slightly higher daily dose,
up to two times that of the first stage, and a progestogen at a
slightly higher daily dosage up to three times that of the first
stage. Thereafter, to adapt to the normal female cycle of about 28
days, no estrogens and progestogens are administered for the
following 5-7 days, for a total of about 28 days. This latter phase
can be without medication of any drug in a conventional manner,
placebos or a non-contraceptive active effective agent can be
administered without adversely affecting the method.
In its composition aspect, this invention relates to a two-stage
oral contraceptive composition consisting essentially of about
21-23 separate dosage units adapted for successive daily oral
ingestion of which the first 10-12 dosage units contain in
admixture with a pharmaceutically acceptable carrier an estrogen
and a progestogen at lower respective dosages, and the next 11-9
dosage units can contain in admixture with a pharmaceutically
acceptable carrier an estrogen and a progestogen at higher
respective dosages, and any remaining units being free of
estrogenic and progestogenic agents.
DETAILED DISCUSSION
By the method of this invention, it is possible to administer lower
doses of estrogen by the sequential method, which is strongly
recommended to physicians, wherein the reduced estrogen dose in the
first application phase still further decreases the estrogen
burden. Also, by increasing the amount of progestogen in the middle
of the administration phase, the occurrence of the normal cycle,
i.e., the normal physiological processes, is initiated. By this
quasi-adaptation to the physiological cycle, the preparations are
more compatible and improved metabolic parameters result.
Furthermore, an optimum control is exerted on the menstrual
cycle.
The term "lower dosage" as used herein means a dose lower, e.g., 60
to 20 %, preferably 50 to 30 %, of the contraceptive dose
conventional for the selected effective estrogen.
The term "higher dosage" as used herein means a dose higher than
that employed in the first stage, up to two times in the case of
the estrogen and up to three times in the case of the progestogen.
Usually this dosage will be 50 to 100 % of the contraceptive dose
conventional for the selected effective agent.
Suitable as the estrogen component for the method of this invention
are the conventional estrogens. In this connection, the estrogen
employed should preferably be administered in such doses that the
amount of estrogen utilized according to the invention in the first
10-12 days is equal to that corresponding to the administration of
0.025 - 0.035 mg. daily of 17.alpha.-ethinylestradiol. The amount
of estrogen utilized according to this invention in the 11-9 days
of the second phase is to be equal to that corresponding to the
administration of about 0.030 - 0.050 mg. daily of
17.alpha.-ethinylestradiol. Inter alia, suitable estrogen
components are also the 17.alpha.-ethinylestradiol esters or
ethers. Furthermore, the natural estrogens can be used, e.g.,
estrone, estradiol or estriol, and the esters thereof, inter alis
estradiol valerate. 17.alpha.-Ethinylestradiol and estradiol
valerate are preferred.
All progestationally active substances are suitable for use as the
progestogen component according to the present invention. In this
connection, the progestogen employed should be applied in such
dosages that the amount of progestogen utilized according to the
invention in the first 10-12 days is equal to that corresponding to
the administration of 0.050 - 0.125 mg. daily of d-norgestrel. The
quantity of progestogen used according to the invention in the 11-9
days of the second phase is to be equal to that corresponding to
the administration of about 0.100 - 0.350 mg. daily of
d-norgestrel.
Suitable as the progestrogen component, inter alia, are
progesterone or the derivatives thereof, e.g.,
17-hydroxyprogester-one esters and 19-nor-17-hydroxyprogesterone
esters, 17.alpha.-ethinyltestosterone, as well as
17.alpha.-ethinyl-19-nortestosterone, and the derivatives thereof.
Derivatives are understood to mean compounds formed with the
introduction of a double bond or double bonds, by substitution, or
by the production of functional derivatives, such as, for example,
esters, ethers, ketals, etc.
The double bonds can be present, inter alia, in the 1(2)-, 6(7)-,
and/or 16(17)-positions. Suitable substituents are, inter alia,
halogen, especially fluorine, chlorine, and bromine atoms, lower
alkyl, especially the methyl group, alkenyl, alkinyl, particularly
the ethinyl group, and/or the hydroxy group, which can be in the
4-, 6-, 7-, 16- and/or 17-positions, as well as methylene groups
which can be in the 1(2)-, 6(7)-, 15(16)- and/or 16(17)-positions.
Suitable esters are the esters of the acids usually employed in the
steroid chemistry for the esterification of the steroid alcohols.
Examples are alkanecarboxylic acids, particularly alkanecarboxylic
acids of 1-7 carbon atoms. Examples for ethers are alkyl and
tetrahydropyranyl ethers. Suitable ketals are, for example, those
of ethanediol or those of the propanediols.
Preferred progestogens are d-norgestrel,
17.alpha.-ethinyl-19-nortestosterone acetate, and cyproterone
acetate.
The progestogen (or estrogen, respectively) contained according to
the invention in the combination with the estrogen (or
progestrogen, respectively) can be the same or also a different one
in the first and second stages. If different progestogens (or
estrogens) are used in the first and second stages, the present
method, in addition to the aforedescribed advantages, has the
further advantage of reducing or eliminating the side effects of a
certain progestogen (or estrogen), in that this progestogen (or
estrogen) is administered merely in one stage, while in the other
stage a different progestogen (or estrogen) having a competitive
array of side effects is administered.
Thus, it is possible, for example, to utilize in one stage the
estrogen in combination with a progestogen derived from
testosterone or 19-nortestosterone and having, in the
17.alpha.-position, optionally a substituted hydrocarbon residue.
These (19-nor)-testosterone derivatives generally exhibit a low
androgenic side effect. In the other stage, the estrogen can then
be employed in combination with a progestogen derived from
progesterone and which does not have the androgenic side effect
inherent in the testosterone or 19-nortestosterone compounds.
Progesterone derivatives having an antiandrogenic side effect in
addition to the progestational effect are considered particularly
advantageous progestogens.
It is also possible, for example, to utilize, in one stage, the
progestogen in combination with an estrogen derived from
17.alpha.-ethinylestradiol. These compounds generally have a lesser
gastric compatibility and a stronger effect on the carbohydrate and
fat metabolism. In the other stage, the progestogen can then be
used in combination with an estrogen derived from the natural
estrogen and which does not have the above-described side
effects.
If different progestogens are utilized in the first and second
stages, a preferred embodiment is to utilize, in the first stage,
the estrogen in combination with a testosterone or
19-nortestosterone derivative and, in the second stage, the
estrogen in combination with a progesterone derivative.
If different estrogens are used in the first and second stages,
preferred embodiment is to utilize, in the first stage, the
progestogen in combination with a 17.alpha.-ethinylestradiol
derivative and, in the second stage, the progestogen in combination
with an estrogen which does not contain a 17.alpha.-ethinyl
group.
The estrogenic and progestational effective agent components are
preferably administered orally, but they can also be applied
separately or parenterally. For this purpose, the effective agents
are processed, together with the additives, vehicles and/or
flavor-ameliorating substances, into the usual forms of application
in accordance with methods known per se. For the preferred oral
administration, especially suitable are tablets, dragees, capsules,
pills, suspensions, or solutions, and for parenteral application,
in particular, oily solutions, such as, for example, sesame oil or
castor oil solutions which can optionally contain additionally a
diluent, such as, e.g., benzyl benzoate or benzyl alcohol.
The oral contraceptive compositions adapted for oral ingestion are
provided as a packaged sequence of unit dosage forms adapted for
oral ingestion of one unit dosage form daily in sequence for 19-23
days, preferbly 21 days, preferably followed in sequence by about
5-7 placebos to provide a total of 28 unit dosages per package. The
unit dosages are preferably packaged in the conventional bubble
plastic package having 28 bubbles in a sheet of flexible plastic
arranged in a oval or circle, each containing a unit dosage with
the placebos being positioned so as to be ingested last. The
bubbles are sealed by a tangible sheet which is adapted to break
and release the unit dosage when the bubble is pressed.
Without further elaboration, it is believed that one skilled in the
art can, using the preceding description, utilize the present
invention to its fullest extent. The following specific embodiments
are, therefore, to be construed as merely illustrative, and not
limitative of the remainder of the disclosure in any way
whatsoever.
EXAMPLE 1 ______________________________________ (Composition of a
Dragee, per Stage) ______________________________________ First
Stage: 0.030 mg. 17.alpha.-Ethinylestradiol 0.050 mg. d-Norgestrel
33.170 mg. Lactose 18.000 mg. Corn starch 2.100 mg.
Polyvinylpyrrolidone 1.650 mg. Talc 55.000 mg. Total weight, which
is supplemented to about 90 mg. with the usual sugar mixture.
Second Stage: 0.040 mg. 17.alpha.-Ethinylestradiol 0.125 mg.
d-Norgestrel 33.085 mg. Lactose 18.000 mg. Corn starch 2.100 mg.
Polyvinylpyrrolidone 1.650 mg. Talc 55.000 mg. Total weight, which
is supplemented to about 90 mg. with the usual sugar mixture.
______________________________________
EXAMPLE 2 ______________________________________ (Composition of a
Tablet, per Stage) ______________________________________ First
Stage: 0.030 mg. 17.alpha.-Ethinylestradiol 1.000 mg.
17.alpha.-Ethinyl-19-nortesto- sterone acetate 32.120 mg. Lactose
18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650 mg.
Talc 0.100 mg. Magnesium stearate 55.000 mg. Total weight, which is
supplemented to about 90 mg. with the usual sugar mixture. Second
Stage: 0.050 mg. 17.alpha.-Ethinylestradiol 2.000 mg.
17.alpha.-Ethinyl-19-nortesto- sterone acetate 31.100 mg. Lactose
18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650 mg.
Talc 0.100 mg. Magnesium stearate 55.000 mg. Total weight,
supplemented to about 90 mg. with the usual sugar mixture.
______________________________________
EXAMPLE 3 ______________________________________ (Composition of a
Tablet, per Stage) ______________________________________ First
Stage: 0.030 mg. 17.alpha.-Ethinylestradiol 1.000 mg.
17.alpha.-Ethinyl-19-nortesto- sterone acetate 32.120 mg. Lactose
18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650 mg.
Talc 0.100 mg. Magnesium stearate 55.000 mg. Total weight, which is
supplemented to about 90 mg. with the usual sugar mixture. Second
Stage: 0.050 mg. 17.alpha.-Ethinylestradiol 2.000 mg. Cyproterone
acetate 31.100 mg. Lactose 18.000 mg. Corn starch 2.100 mg.
Polyvinylpyrrolidone 1.650 mg. Talc 0.100 mg. Magnesium stearate
55.000 mg. Total weight, which is supplemented to about 90 mg. with
the usual sugar mixture. ______________________________________
EXAMPLE 4 ______________________________________ (Composition of a
Dragee, per Stage) ______________________________________ First
Stage: 1.800 mg. Estradiol valerate 0.100 mg. d-Norgestrel 31.350
mg. Lactose 18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone
1.650 mg. Talc 55.000 mg. Total weight, which is supplemented with
the usual sugar mixture to about 90 mg. Second Stage: 2.400 mg.
Estradiol valerate 0.120 mg. 17-Acetoxy-18-methyl-15.alpha.,
16.alpha.-methylene-19-nor-4- pregnene-3,20-dione 30.780 mg.
Lactose 18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.600
mg. Talc 55.000 mg. Total weight, which is supplemented with the
usual sugar mixture to about 90 mg.
______________________________________
EXAMPLE 5 ______________________________________ (Composition of a
Dragee, per Stage) ______________________________________ First
Stage: 1.800 mg. Estradiol valerate 0.100 mg. d-Norgestrel 31.350
mg. Lactose 18.000 mg. Corn starch 2.100 mg. Polyvinylpyrrolidone
1.650 mg. Talc 55.000 mg. Total weight, which is supplemented with
the usual sugar mixture to about 90 mg. Second Stage: 2.000 mg.
Estradiol valerate 0.150 mg. d-Norgestrel 31.100 mg. Lactose 18.000
mg. Corn starch 2.100 mg. Polyvinylpyrrolidone 1.650 mg. Talc
55.000 mg. Total weight, which is supplemented with the usual sugar
mixture to 90 mg. ______________________________________
CLINICAL TESTS
EXAMPLE 6
The first stage of preparation according to Example 5 was
administered to each of five women of child-bearing age daily for
11 days (first stage) and the second stage thereof was administered
daily for the following 10 days (second stage). The subsequent 7
days, during which the menstrual bleeding occurred, were without
administration.
During the entire treatment period, the cycles were anovulatory.
The preparation was of excellent compatibility; the number of
intermediate and spot bleeding was considerably reduced as compared
to these occurrences prior to treatment; the side effects were
likewise, in part, markedly reduced as compared to the last cycle
prior to treatment.
* * * * *